Mitofusin agonists to prevent Charcot-Marie-Tooth disease 2A Gerald W Dorn II, MD Mitochondria in Motion, Inc. Washington University in St Louis School of Medicine Abstract: Charcot-Marie-Tooth (CMT) disease type 2A is an incurable, primarily pediatric, autosomal dominant neuromuscular degenerative disease caused by mutations in the mitofusin (MFN) 2 gene. There are currently no disease-altering treatments. Mitochondria in Motion, Inc. will develop and produce investigational first-in-class small molecule mitofusin agonists, under an FDA approved IND, to treat CMT2A and other neurological diseases. Mitofusin agonists enhance mitochondrial fitness, metabolism, and trafficking within cells, thus improving homeostatic functioning and injury-responses of neurons adversely impacted by MFN2 genetic mutations. Here, we hypothesized that activating endogenous, genetically normal MFN2 and MFN1 will reverse dominant inhibition by CMT2A MFN2 mutants of neuronal mitochondrial fusion and trafficking, thus delaying or preventing CMT2A-induced neuromuscular degeneration. Our immediate goals are to refine our lead mitofusin agonist for in vivo administration (SA#1) and to provide proof-of-concept for in vivo mitofusin agonist efficacy in a mouse model of aggressive CMT2A (SA#2) to support our preclinical data in CMT2A patient- derived cells. We will fill an unmet healthcare need and build a commercial enterprise to serve the ~10,000 Americans with CMT2A and the >200,000 Americans suffering from other neurodegenerative diseases characterized by mitochondrial degeneration, including CMT type 1, amyotrophic lateral sclerosis, and Huntington?s disease. Our deliverable in this 1 year Phase I STTR will be a mitofusin agonist(s) ready for STTR Phase II IND-enabling studies in CMT2A and validation in an expanded number of orphan diseases, in preparation for anticipated first-in-human trials.